HIV pharmacology: How to get data quickly to decide – Interview with David Back

“I think the issue that we always want to address is risk benefit of any therapy, be it a single drug or a regimen, and a major principle is that you want the benefit to clearly outweigh the risk- states David Back, Professor of Pharmacology, Department of Molecular & Clinical Pharmacology at the University of Liverpool, starting our conversation about new possible paradigms in HIV therapy. Every time we have new drugs in the market we start to think how to change or innovate: we have to save the way towards innovation as well as the way towards standard therapy. In any case tolerability remains the main issue… We know that there are adverse effects, we have seen adverse effects, if we go back through the development, for example, of the nucleoside analogues, the D drugs were always drugs that concerned us about mitochondrial toxicity, which then linked through to lipodystrophy, so we have got better, I think at understanding some of the key areas. We then had abacavir hypersensitivity of course with the nuke, and we understood the basis of abacavir hypersensitivity brought in the HLAB* 5701 testing. When you look at the other classes of drugs, I think now we are more concerned about long-term toxicity, so that we think of tenofovir and what are the implications of small changes which are seen in renal function and the odd case report of Fanconi syndrome… We are concerned long term and we have new drugs, so that the tenofovir GS-7340, which is the new form of tenofovir, if you like, which is a pro-drug looks an exciting drug but we have a lot to learn. I think we have learned but we are learning and we need to continue to learn.
In these periods there is lot of noise about dual therapy and monotherapy…
Yes. So, the basic principle has always been that you have to have enough drugs in the regimen to suppress the virus and we learned very early on that combination therapy clearly was the way forward. What I think has now gradually emerged is that, once you suppress the virus, the question then is can you maintain the suppression of the viral load by reducing the number of drugs in their regimen, if you really need to have three drugs, what about two drugs and even then… Of course, we have monotherapy studies with one drug.
It’s an area that has caused a degree of polarization of views, not everyone has agreed that this is the way that we need to proceed, but we clearly have data which suggests that there are certain areas that we can use, maybe reduced numbers of drugs.

What kind of parameters we have to consider in order to make therapy easier and simply?

As far as dose simplification is concerned, one is looking all the time to make a regimen as simple as possible for the patient so that patient will be adherent to the therapy, that’s a key, adherence to therapy, and to maintain a reduced impact of any adverse effects. So, simplification of therapy, which is why with Atripla, for example, one pill once a day, with the new Quad which will emerge is one pill once a day, and fixed-dose combinations being the simplest type of regimen. In a sense, if you got a fixed dose at one pill once a day, you could argue it doesn’t matter whether there are three drugs in that one pill or whether there is only one drug in that one pill because you got a simpler regimen which is much easier for the patient to take, as long as you haven’t got adverse effects and intolerability issues. We know that tolerability issues have revolved to a large extent around certain drugs: ritonavir has always been a tolerability question mark in people’s minds because of the diarrhea, the gastrointestinal effects, etcetera. Will cobicistat, the new booster, be any better? I think time will tell, there is always an excitement around a new drug but then there is always the realization that at this moment in time there is no perfect drug: every drug has got its benefits and we have to work out what the issues are around some of the side effects.

In planning a chronic therapy, in oncology it’s used a concept of induction and maintenance, do you think that also in the HIV field we should use a similar approach?

Logically, that should work in my view. If you can induce and make sure the patient’s virus is suppressed, can you then suppress it with less drug or less numbers of drugs.
Clearly the clinical data will always be the key that we rely on, it’s not just a theory, it’s got to be shown in practice in long-term, three-year, five-year trials. You can really suppress the viral load with, if you are going to reduce the number of drugs in that regimen you really got to make sure that is true, but there are data to suggest that we can do that under certain circumstances, but it’s not, you have to define which patients will benefit by that strategy.

The simplification approach is a good tool in order to deal with the aging process caused by HV and occurring as overall effect in HIV/AIDS people that – because of HAART- are living longer…

Aging is a real challenge as well because there are so many changes taking place with aging. There are changes in the way that the body handles the drugs, the body responds to the drugs, the implication of maybe increased adverse reactions to the drugs, there are all the co-morbidities that are been treated as well, so one has to think as patients get older of strategies to maintain the optimum management.
From my clinical pharmacological background, it is always optimize the management of the patient who is in front of you: it is not just looking at patients as a group, it’s always to say can we do better for an individual patient and I think that is the way that we have to look.

In this context, also polypharmacy is a key issue.

Sure, polypharmacy is a key issue. We did a survey recently with a Swiss cohort of over 50s and under 50s in terms of the number of co-medications and, unsurprisingly, if you are over 50 you are on more other medications for co-morbidities, particularly around cardiovascular disease, so in terms of high blood pressure treatment, in terms of lipid lowering agents, there were clear differences between the under 50s and the over 50s. In that context, you have to think about the co-morbidities being treated and what drugs can you use, what drugs would be unadvisable to use because of drug-drug interactions, which is still an area that we have to manage well and manage better with all drug interactions: indeed, aging is an issue.

Last question is related to CNS. We don’t have so many drugs that are able to reach the HIV everywhere where is replicating.

No, that is true. It’s clear, the data that we have comes from CSF, so that we look at penetration into the CSF and then the debate is “is a drug in the CSF necessarily the same as a drug actually in brain tissue” and all the different considerations that we need to think about because we know that some drugs can penetrate into the CSF, other drugs don’t seem to penetrate so well into the CSF. But we have to then think about all the drugs in a regimen: do you need all three drugs or maybe you can have less in terms of the regimen as long as you have got really effective drugs, because you got low viral replication.
Again: I think there is a lot we don’t know and we sometimes tend to extrapolate beyond what we do know. The challenge is going to be, particularly with the new drugs coming through, of getting the data quickly, which will enable us to understand better and CNS penetration is one major issue. I think that is an issue which for CNS penetration is: is that one drug going to penetrate into the CNS, and it’s not just the CNS, it is to all sites where there potentially is virus. For example, there is a recent study looking at GALT biopsies, where apparently atazanavir didn’t seem to penetrate into the GALT tissue. So, there is ongoing studies where I think, as long as we can look at the virology and the pharmacology together, we will get a greater understanding of tissue penetration and tissue localization of drugs.

Article found in – HAART and correlated pathologies n. 15

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In a crowded sea, sailing toward a brave new (HIV/AIDS) land

The great number of antiretrovirals available to set up a potent end durable therapy poses many questions in terms of decision. We are not referring to solutions as defined by guidelines, that usually define a sort of “standard way to deal with”. We are more interested to explore strategies of innovation that could arise from different approaches that take into account which drugs we could use in a different way, taking into account the main issues we are facing in these hard days. On one side we have financial constraint –it’s true-, but on the other side we are sitting on a great success: HIV/AIDS is now a chronic condition; the therapeutic armamentarium is crowded and neither potency neither efficacy are still on discussion. On stage, there are key issues like compartmentalization, simplification, future options and –mainly- safety.
In order to address these issues we met four experts in order to speculate –on the ground on the present data- which could be the spaces for different, may be future, options in terms of strategies dealing with HIV as chronic infection and HAART as chronic therapy.
We chose the experts from different fields (and persona attitude) in order to draw the picture as complete as possible: David Back because he is the leading expert in terms of HIV/AIDS pharmacology applied to clinical decision; José Gatell, because he is a clinicians who worked in HIV/AIDS since the beginning; Mark Weinberg because he is a basic science researcher working on translational approach, also adopting radical positions: he was one of the first to claim for microbiocides and now –once again- he is supporting a non-traditional use of antiretrovirals like PREP (as you can read in the box, pag x); Mark Nelson, a real provocative clinician who seek to define innovative way to deal with ARV, lying in the tradition –as only an English man can do.
The following pages aim to be an open door to the possible and to the future: a door that could be used by anyone of our readers, who wants to say something and adding his/her opinion about these topics.
Closing this issue of HAART FDA decided to approve the first drug to prevent HIV infection.
We had already decided to put a box on this “non conventional use of ARV”. We will be back on this topic for many reasons, not only medical but also sociological and cultural.
Everyone who would send us his/her comment on PREP and FDA approval to join the forum will be welcome.

Article found in – HAART and correlated pathologies n. 15

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Toxicity vs. tolerance: how pharmacogenomic could help – Interview with Amalio Telenti

This is the crude statement that could summarize my talk with Amalio Telenti, professor of Medical Virology at University Hospital and University of Lausanne, in Switzerland. This year he had the opportunity to draw the state of the art of genomics research in HIV/AIDS during the CROI in Seattle and after during the ISHEID conference in Marseille, where he accepted to answer to my questions. Despite progress and relevant amount of publications the use of genomic tools to make easier decision and simplify the daily life of a person dealing with his/her own therapy, in your talk said that genetics is everywhere except in the clinic Yes, I think that was the common motive to my talk. It is to express how as much as it comes out of daily press and there is lots of hopes and there is a lot of interest also outside of the medical environment, surprisingly we are not seeing much of it coming to us, either because it’s not ready or because there is something wrong in the way we are bringing those tools into our help.

In the HIV field, you started working on genomics since 2005. I remember during the IAS conference in Rio you told me the future of this approach. Now, 7 years later, you have lot of new data you have presented in your talk, focusing on individual answer to every specific drug… I think we have to think that, as much as we are all different, we are also different in terms of how we metabolize drugs, how we develop toxicities and some of it is coded and it can be traced back with the new technology to particular genes. Some of the genes are very good at predicting, almost black and white: a particular problem like for example the famous abacavir hypersensitivity and a type of HLA.Some of the genes contribute a small information, but information could be useful.

For example your patient may develop diabetes, if you put him on this drug. It’s very hard to re-educate all the medical community on how to use a large number of new tools, new tests and which one is very good, which one is a bit informative. I think the challenge will be this new generation of physicians that will probably have to slowly integrate predictors in their clinics.

In your talk, you discussed the position of pharmaceutical companies and the perception of the medical doctors vs. the perception of patients.
I think there are important issues to be discussed in our community – doctors, healthcare workers, patients – in what is acceptable toxicity and this can be what the doctors look for. Big things: you don’t want to do harm to a patient, but then when we go away from the big things, we stop listening to the patient, we don’t want the patient to be whining because they don’t sleep well or because they get sad or because they say that their body is changing. Why? Because, of course, accepting those minor complaints will force us to consider new therapies, change therapies, so we just push it away. Now, when you observe the behavior of patients in retrospect, you will realize that if they are given the choice they will drop drugs not because of major toxicity, but just because it doesn’t feel well. In my opinion this is a field where pharmacogenetics could help. Companies don’t want to hear about it because they don’t want their drugs to be pushed aside just by what they call minor adverse events. Doctors don’t want to be busy changing drugs for what they also consider as a kind of minor problems of a therapy, that otherwise works wonderfully against the virus. So, the whole system is built to ignore that therapy may not be well tolerated and that there could be alternatives.

It’s interesting the concept “toxicity vs. tolerance” you have used in your talk…

I think I hope that we think about that: toxicity is what is in the doctor’s head, tolerance is what is in the patient’s head and these two worlds have to reconcile.

The Food and Drug Administration recommends some kind of genetic tests in order to start a therapy with some drugs, the NIAID has said that it could be useful if everybody enrolled in clinical trials will give informed consent about to storage their DNA. Why it’s so difficult to obtain this?
I think because there is still this deep-rooted feeling that genetics is a violation of our last level of privacy and therefore either ethics commissions, patients, countries will oppose what is required, that means a storage, long-term storage and large-scale screening, it makes no sense to ask permission to analyze one gene, it makes sense to ask permission to analyze a whole genome.
Therefore, somehow people say I am exposing myself excessively and this is a risk, or perceived risk, insurance, etcetera. The idea is to try to convince society that when you spend half a billion or one billion to put a drug in the market, the minimum that you can do is already from the beginning try to identify those people that may pay a heavy price from receiving that drug because they will die of a hypersensitivity reaction or a toxicity of the liver or they will accumulate a particular distressing syndrome or will not respond. Now, this is a change in mentality. A clinical trial should attempt to understand the origin and basis of failure or of toxicity from the start, not five years later. Academic groups like ours will try to catch up and try to figure out in retrospect why people were getting a particular problem. This has to be built into the system and, as I mentioned in my talk, there are excellent examples, like for example IL28b, the interferon lambda, and interferon response excellent exemple of successful use of clinical trial materials to find something that is very important for people: am I going to respond to interferon or not? Is it worth to start a costly treatment for something where I know already I will not respond?
It’s a way to maintain the promise of less drugs more efficient.

This is a war of the movements where the pharmaceutical companies have not decided: are we asking pharmaceutical companies to produce drugs for everybody?
Are we asking them to produce effective drugs for some people? Of course, these are two competing economic models and eventually somebody will have to figure out what makes sense in terms of society or economically. Is it cheaper to pay for toxicities or is it cheaper to pay for individualization?

Article found in – HAART and correlated pathologies n. 15

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Editorial Renaissance and/or Baroque?

Let’s say that this issue of HAART is on drugs and how to use drugs at the best. It is for HIV infection as well as for HCV.
We know that every virus tells its story, but some similarities could be found, especially if you think about the process of drug discovery and the knowledge spread about it use. The impact of having efficient drugs in HIV and HCV is similar: we have to face epidemics on a global scale, to prevent the contagious, to reduce the burden to the disease and to cure the infection. Ideally, we would end the epidemic.
All of this needs drugs and we do have antivirals: we call HAART the combination of them to treat HIV infection; we call DAA the new compounds that address directly HCV the process of replication. It is a impressive condition that was unthinkable only some years ago, making improvements day by day. Drug are thought as the main surrogate of health, “the” solution to restore a condition that is not balanced, the answer you can swallow in order to face a threat.
A substance becomes a drug when there is a person who intake it for some expected effect that the above mentioned substance should have –either if it’s supposed to have, either it has demonstrated to have. A substance without a person cannot be a drug. It remains a powerful substance, but not a drug. Drugs –pharmaceuticals- are at the heart of the story of HIV infection. Drugs, the quest for an antiretroviral was the first question that was made by people that were in need. Because to our culture drug –a pill- could be the answer: it reflects a specific cultural approach to formulate and to think a problem a in a specific way that includes -at some extent- in itself the answer. If we understands how it works, then we can built the solution. HIV was the first big challenge to this. I’m referring, for instance, to the too much optimistic statement made during a memorable press conference in April 1984 by Margaret Heckler, US Health and Human Services Secretary, after -may be- having had a conversation with the virus’s co-discoverer Robert Gallo: “We hope to have a vaccine ready for testing in about two years”. Now, 30 year after, we don’t have any licensed vaccine (we have only some people claiming that have got it). But we have drugs and HAART, and it impact on prevention.
As said last year during the IAS conference in Rome the director of the US National Institute of Allergy and Infectious Diseases (NIAID) Anthony Fauci “I’ve never seen something explode like this”, commenting the results of HPTN052: earlier ARV treatment of HIV-infected individuals leads to a dramatic 96% decrease in HIV transmission. And the results of Partners PrEP and TDF2 showed that pre-exposure prophylaxis (PrEP)— ARVs to HIV-uninfected individuals— resulted in a 62%-73% reduction in HIV transmission among heterosexual men and women. Also without a vaccine we could stop the epidemic, may be, but Adherence appears to be a critical factor for PrEP protection against HIV.
How we were able to be here? We cannot forget the tremendous role played by activist on making pressure on R&D department in Pharma as well as in public health sectors. At the very beginning of the epidemic we have seen a contradictory behavior: those who were afraid by toxicity and by the medicalisation –including anxieties for the growingup role of pharmaceutical companies-, saying that there is any link between medical sciences and society, and those who were claiming -writing it on their panels- “make tomorrow happen today” and “drugs into our body”, a sort of utopist republic of anti HIV drugs.
Pharmaceutical drugs represent a unique opportunity to study the relationship between symbol and political economy considering drugs as commodities with their distinctive biographies – considering in this case biography as metaphor: “people give these substance a history. As powerful technical devices and status symbols, medicine acquire a status and force in society” (2). “Following the transaction of these object reveals biographical order –and a gendered technical order- to their social life. Pharmaceuticals may profoundly transform social relations, thus rendering useful a consideration of politics –understood as various struggles shaped by power and its operations” (3).
HIV field with its antiretroviral access programs – especially in middle income countries- considering aspects like adherence to treatments and perspective for the future, point to innovative forms of socio-political identification and participation focused on the concept of the therapeutic or biological citizenship (including the right to health care) (4).
We know that every virus tell us a different story, but the history of HIV and the history of drugs development could be useful for those who are working in Hepatitis field –both for physicians and activists. As explanation of the reason why we have a huge number of compound that are now in the HCV pipe line, Markus Peck-Radosavljevic, associate professor of medicine at the Department of Gastroenterology and Hepatology at the Medizinische Universität Wien, told us that “hepatitis C research is really tremendously benefitting from HIV research because a lot of what is known about viral kinetics and so on was learned from the HIV community. The second and really major breakthrough for hepatitis C research was the so-called “replicon system” at the turn of the century, developed in 1999 actually, before that it was not able to grow the virus in culture, so it was not able to test targeted agents in a culture system which made drug development incredibly difficult because you could only grow the virus in chimpanzees outside the human beings and that was very difficult. Now, with the replicon system, out of a sudden you could test drugs in a petri dish and that’s what started the revolution”. (see his interview at pag XX).
We have getting solution for HCV infection, in a short period also without interferon. And In HIV field we are in the privileged position to define new strategy, because we have so many efficient ARVs. “I think we need to start thinking about novel ways of treating patients. I think what is going on is that we have all become rather routine prescribers just writing out our favorite prescription for the majority of patients- says in a very passionate way Mark Nelson, Director for the HIV Directorate and Deputy Director of Research, Chelsea and Westminster Hospital:- so we need to think about the necessity to individualize per patient: we need to consider the pros and cons for the individual patient”. (see his interview at pag XX).
Now a fully trust on drugs now arise also from some of those who were critics against the “republic of Pharma”. And at the same time we can listen that people who were in favour of early use of drugs are now claiming against PrEP. It is all too new in order to solve the puzzle, in which stands the FDA decision to approve the first drug to prevent HIV infection.
We need to the bate all these issues related to the non conventional use of ARV.
Somebody suggested that we are living may be in a sort of antiviral Renaissance. I think it could be a nice definition of the very recent period, until now. With the PrEP revolution we are entering a in new phase, may be: let’s call the Baroque. If Renaissance means in art and philosophy the use of the geometrical perspective and the human being as measure of everything, fully trust in human mind and its ability, Baroque –that comes against Reform as the need to reaffirm the supremacy of Catholic Church as prescriptive core behavior and values- means emphasis for “decoration” and expression of the power. Today it’s seem that the (wonderful) power of the drugs is founding a new one-way rationality of behavior, that must be based on adherence. Let’s ask in a provocative way: is it the beginning of the era in which pharmacopeia will represent the only accepted manners and etiquette? We are open to publish all the answers you have.

Article found in – HAART and correlated pathologies n. 15

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DAAs drug-drug interaction

Every time we are facing an innovation, we have to be prepare to deal with the issues arising from the novelty. In the pharma field, dealing with complex regimes treating chronic conditions is drug-drug interactions.
In order to define the state of the art of the pharmacological interactions of the new protease inhibitors against HCV I have met David Back, Professor of Pharmacology at the University of Liverpool, one of the leading scientist in this field. Last February professor Back was invited in Rome by the faculty of the Associazione Italiana Studio Fegato for the AISF annual meeting.
The common feeling is that we are at the beginning of a new era also for the drugs against hepatitis C….
“Drug-drug interactions definitely represents a challenge for us, with the new directly-acting antivirals.
We have understanding of telaprevir and boceprevir that there are going to be a number of clear drug interactions that we will have to be watching for. This is because both of those drugs are potent inhibitors of one of the key enzymes for the way that drugs are handled in the body, cytochrome P453A. To a greater or a lesser extent, drugs that are metabolized by that enzyme are going to show drug interaction: that is the area that we are going to be concerned about.

During your speech at the 45th AISF Annual meeting you listed the different drug interactions for the two new drugs we are going to have in the clinical practice. We can start with telaprevir… With telaprevir there are a number of drug interactionstudies which have been done which have shown the potential problems that we face. So, for example, with immunosuppressants, which are key for transplant patients, the magnitude of the interaction with both cyclosporine and tacrolimus is such that we are going to have really careful management of dosing for those particular drugs. In one sense, what we would like to say, where there is a large interaction, is let’s use alternatives, but there are challenges because often there are no clear alternatives that we can use and so, we have to manage those interactions.

From an HIV background, which is where I come from, we are used to managing interactions in HIV. The challenge for hepatologists is to be able to think differently, because with peginterferon and ribavirin there are virtually no clinically relevant drug interactions, one or two at the most. With the DAAs, there are going to be a number, and there are going to be some comeds that are contraindicated, there are going to be some that we will have to be very cautious.
With telaprevir I highlighted some of the key areas that we are concerned about, where there will be contraindications, often with some cardiovascular drugs, and there will be others where we will have to manage those interactions with caution, starting with dose modification and then titrating to effect.

And with boceprevir?

Boceprevir has an additional way that the body gets rid of it. So, there is an enzyme called aldoketoreductase, which also handles boceprevir, metabolizes boceprevir, but it’s not going to rule out drug interactions at all. So, although the magnitude of the interaction with immunosuppressants is slightly less and with midazolam, for example, and with some of the statins, it still means that there are going to be contraindications for boceprevir, and there are going to be the areas that we’ll have to start with a dose, the lowest dose that we can, and gradually titrate to the effect. We are on a steep learning curve, we have a limited number of drug interaction studies done, what we now need to do is to begin to understand those drugs that we can’t do studies with, but we are going to have to use in our patients and that’s where I think pharmacologists, discussing with hepatologists and getting groups of people together to really understand how we can best manage the patients.

Taking into account also the HIV coinfection…

HIV coinfection is a specific issue. So, for example, just two weeks ago Merck issued a statement based on pharmacokinetic data for boceprevir, where the magnitude of the interaction of the HIV drugs with the HCV boceprevir drug meant that the extent of that interaction would rule out, being able to coprescribe atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, key drugs, key protease inhibitors for HIV, with boceprevir. So, what we need to then understand is which HIV drugs can we use in coinfected patients, and at the moment a drug like raltegravir has limited interactions, efavirenz is probably going to be a drug that we can use maybe with some dose modification, which has happened with telaprevir, but again: we are on that steep learning curve, we got new data and we now have to under stand how with the new data we can best use the drugs in coinfected patients.

And there is another issue that covers both drugs that are methadone interactions, because we have a lot of patients with HCV that have a story of intravenous drug use.

Yes, so methadone, that’s a key interaction: the good news I think with methadone is that, although there is a change in the exposure of methadone which would initially lead us to think you’d need to modify doses and cause changes in the stable dosing that one would use. In fact, because of some complication of protein binding which I won’t go into in detail, it seems that we don’t need to modify methadone with telaprevir, whether we do with boceprevir at this moment is not clear, but I suspect not. My understanding from the data we have is that methadone we can use pretty much without any dose modification.

As you have already done and established in the HIV field, you are running a website that could be a good help for the clinical practice.

I think it’s critical that we have the information available, so we have set up a website for hepatitis drug interactions which is populated with all the new information that comes from conferences, papers and with an expert editorial board inputting into the website.
What we are going to try to do is to make sure that it is as comprehensive as possible. One of the questions that arose during the discussion after my talk is “can you tell us which drugs we can’t use?”, and what we hope to do with the website is to give clear guidance as to which drugs are not to be used and what alternatives, where there is contraindications, what alternatives can we use in our patients and by doing that we hope that this will be a useful resource for the community. We can’t remember all drug interactions, I work in drug interactions, I can’t remember them, I need help and I need resources.
So, we have a website and from the website you can download for the iPad and for Android resources and iPhone resources, so it’s something that will be useful we hope.

As we said at the beginning of this conversation, we are at the beginning of a new era for hepatitis C treatments, with an impressive pipe line of new drugs.

How can you explain the reason why so many drugs in so small portion of time for hepatitis C? When you look at the pipeline and you see some people quote 60, 70, 80, 90 new drugs in that pipeline, it’s an exciting field to be in. When one considers 170 million people with HCV coinfection, clearly there is a huge potential and we know that we can cure this disease as well. We have started the process with the two new DAAs, we are going to get better drugs, we are going to get drugs that are easier to use. I mean what we are using at the moment, the drugs three time a day in high doses: we want to go to once-daily drugs and potentially then to remove pegylated interferon and ribavirin and those sort of issues are big issues for discussion at the present time and in clinical trial.

The numbers of people affected by this virus maybe is not enough to explain so many drugs because, for instance, for hepatitis B infection affects more people around the world…

Sure. I guess that, I am not from a pharmaceutical background, but when one looks at the pharmaceutical companies and realizes that virtually all the companies now have a big program in HCV with new drugs…we know that some drugs are going to fall by the wayside, that’s the nature of pharmaceutical company development, but I do think it’s an exciting pipeline with an exciting potential for us to really revolutionize the way that we treat hepatitis C. Given the drug interactions which I have described for the two, telaprevir and boceprevir, hopefully we are going to get drugs where we don’t have so many drug interactions and the usefulness would therefore be I think even greater.

Article found in – HAART and correlated pathologies n. 14

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HBV: a global threat, bus with less attention paid – Interview with Robert Perrillo

Robert Perrillo is the Associate Director of Hepatology at Baylor University Medical Center at Dallas and Director of the Hepatology Fellowship Program. Dr. Perrillo is internationally recognized for his work on antiviral therapy of chronic hepatitis B and the scientist that AASLD suggested me in order to have a talk about hepatitis B. I met him in San Francisco during the Liver meeting.

This 2011 seems to be the year of hepatitis. There is a lot effort in order to increase awareness about hepatitis C and hepatitis B all over the world. Here, during the Liver meeting i there were two sessions devoted to the global program against hepatitis, one driven by CDC and the other one together with NIAID. But many of the noise rased is realted to HCV. About hepatitis B, where we are?

Well, hepatitis B is a condition that afflicts 400 million people worldwide and I think that the United Stated has been considered traditionally as a low-incidence area, a low-risk geographic region. But now we all of the practicing physicians who see such patients are noticing that we are seeing a lot more patients who are of the immigrant populations to the United States, not just Asian Americans, but also those from the continent of Africa and also those from the Eastern European nations, who have immigrated here and have brought hepatitis B with them. So, the prevalence for hepatitis B in the United States has been traditionally underestimated: it is probably above 2 million people. Now, that pales in comparison to hepatitis C where we think it’s more like 4 million people, but both of these conditions are very significant. Hepatitis B, like hepatitis C, can establish a chronic carrier state and can lead to cirrhosis and liver cancer and actually is a leading cause of death in people that have the affliction of hepatitis B from early in their life, where 15% or more of adult, generally younger males in their middle ages can have a decompensating form of liver disease or liver cancer, so it must be taken seriously. The two major types of therapeutic agents that we have available to treat it are an injectable material called interferon, which is also currently being used as part of a triple therapy regimen for hepatitis C. Interferon has been a license for hepatitis B for approximately 18 years now, and it tends to be not utilized, because of some adverse events. Into the past five years, we had availability of nucleoside analogues or nucleotide analogues: pills that can be taken orally, once a day, and they inhibit and suppress hepatitis B virus. Interferon, unlike the oral drugs, actually augments cell-mediated immunity against hepatitis B and therefore the state of the art is moving towards a direction of looking at combination therapy, where we are using interferon to stimulate immune responses against the virus in conjunction with a potent suppressive agent that can be taken orally. First past studies, five-six years ago, looked at interferon with a less than completely effective nucleotide analogue and so these studies where not definitive by their very nature. We now have oral drugs, such as tenofovir and entecavir, that can be taken with a very slight risk of developing drug resistance, then had stymied us in the past and prevented us looking at monotherapy as a long-term kind of beneficial way of treating the infection. Unfortunately, the problem with the nucleosides still remains: they are only effective as long as you take them. So, there is indefinite treatment needed, sometimes you could conceive of this as being in excess of six or ten years while waiting for the markers to change sufficiently that you would be able to stop therapy, so we don’t really know when we can stop in many patients. The combination of interferon and a nucleoside offers the option to come up with a higherquality response, perhaps getting down to even minute levels of virus remaining in the liver tissue and for all intents and purposes coming as close to a clinical cure of the disease as we come.

This is the reason why we need the new drugs? Yes, we need new drugs all the time.

The biggest gap of what we really need is a drug that like interferon can stimulate the immune response against the virus, get to a greater state of viral elimination and yet not have the unpleasant side effects. So, the magic bullet for the future will be an immunostimulatory compound that doesn’t have a lot of side effects.

Notwithstanding, until we come up with such a drug, the combination of interferon and nucleoside analogue therapy can be an effective tool that we hope will bear fruit.
There are many studies ongoing now to look at this, sometimes these studies use the drugs simultaneously, sometimes there is a leadin with the interferon to induce an immune active state before you add on the viral suppressive agent. In some studies they are looking at people that have been on the oral pills for a while and haven’t come to a complete satisfactory response where you’d feel comfortable stopping: so they had interferon on the trailing edge of that therapy to see if they can come to a higher-quality response where you can lose the hepatitis B surface antigen, which is the outside envelope of the virus, at which point you can be pretty sure you that are going to have a long-term response if you stop the therapy. I think the field is exciting, there aren’t as many new drugs being developed as in hepatitis C, but we are coming to a far better understanding of how to use the existing drugs for hepatitis B.

The issues you have mention explain why adherence is a key issue in the management of a patient with HBV…

Adherence will always be an issue, whether you are taking one pill or four pills a day, because of the human character. Hepatitis B and C are often asymptomatic or minimally symptomatic, so it’s hard to stay with a relatively costly drug therapy for an indefinite period, which is what we often do with hepatitis B, hepatitis C has more time-defined therapy, so we have side effects but we hope to get the patients through before the side effects become limiting. With hepatitis B, with the oral drugs that we have, we don’t have side effects, we do have cost, we do have an asymptomatic condition.
Unfortunately, there is an undeserved stigma from having hepatitis B. Many people who are in the immigrant populations who have it would rather not have it and cause concern for their family members, as well as the cost of care. In fact, the sad truth is that in hepatitis B we estimate that at least 50% of the people in the US are foreign born who have it and these are people that don’t always have the greatest access to care, so as a result we can’t reach the net out there, the health net to treat these people very effectively, there are cultural barriers against seeing doctors for this condition. Diabetes, hypertension and high cholesterol get more attention that hepatitis B which can be life threatening over a long period of time.

Article found in – HAART and correlated pathologies n. 13

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A future without interferon? – Interview with Jaen-Michel Pawlotsky

“I would say major scientific progress, modest humankind progress”, said to me Jaen- Michel Pawlotsky, Department Head of Virology at the Hospital Henri Mondor, Cretteil, in France: this could be the synthesis of the gap between the social burden of hepatitis and the outcomes of medical advances in this field. It is a realistic statement and it underlines that sometimes science and research go faster that social consciousness and policies. This year World Health Organization celebrated the first Hepatitis World Day, and it was after a deep lobby activity started some years ago together by the international scientific societies -EASLD and AASLD- and the patient based organization World Hepatitis Alliance. Now there is a WHO resolution that recognize viral hepatitis as global threat, a public health concern. I had the opportunity to met prof. Pawlotsky during last Liver meeting in San Francisco, immediately after the speech he gave to the conference.
“Well, things have changed a lot scientifically. In terms of making priorities and improving screening and access to care things are going much slower and I think this is a kind of dissociation we are seeing in this field right now. The science is evolving very rapidly, we will probably discuss a number of advances that have been made, progresses are made in terms of new drugs coming, interferon-free regimen, etcetera, etcetera. Now, the global awareness of the problem, the knowledge that 130 million people are infected with HCV, active campaign for screening and ensuring access to care to these patients with the old drugs and eventually with the new drugs in future is something that I think is going very slowly and very late”.

How we can describe the global burden of viral hepatitis?

Currently we estimate that 130 million people are infected with the hepatitis C virus worldwide, 350 million people are infected with the hepatitis B virus worldwide. Not everybody has access to therapy, for those who have access to therapy it’s easy to control hepatitis B, you don’t cure hepatitis B but you can control it with the drugs we have, entecavir, tenofovir.

We see better and better treatments with hepatitis C and a lot of new data with very high cure rates but, again, I would like to insist on the fact that access to care, screening, active campaigns for screening and identifying patients and giving them the opportunity to have their disease controlled is going very slow and there are areas of the world where virtually nothing is done and I think that’s a major issue that our community, the viral hepatitis hepatology community will have to tackle in the future.

Having a vaccine for the hepatitis B means that it is feasible the idea to eradicate hepatitis B virus from the world?

Yes, the vaccine is a very active one, it’s very safe, it’s something which works very well, the problem is that you have two steps. If you start vaccinating newborns, which is done in many areas of the world, you really decrease the burden of the disease and this is what is happening in China right now, they have been able through their vaccination campaign to reduce the burden of HBV infections in young people tremendously, but you still have the old ones who are infected. So, your approach must be a double approach: you must obviously improve vaccination coverage all over the world, but you must also take care of the patients who have acquired the infection, are chronically infected and may need therapy. And this is a little bit of a challenge, vaccination is generally relatively cheap and very cost effective as a strategy, antiviral therapy is costly and this does not work everywhere and different countries have adopted different approaches for that.

For hepatitis C, we don’t have any vaccine, but we are staring to have so many drugs..

I think what we have learned over the past few months, or weeks or even days here at this meeting, that it’s very easy to cure infection, but we didn’t have the right drugs to do that so far. Now these drugs are coming and we see that with good drugs. What is a good drug? It’s a drug that is potent and has a high barrier to resistance, if you can sustain inhibition of viral replication for a few weeks, two months, you’ll get to a cure. So, it’s an easy-to-cure infection, the issue of vaccination is a different one. The point is that it’s very difficult to develop a vaccine for this virus because of the immunology of this virus, the fact that it is highly variable, that infection does not protect against a new infection and there are other issues which is it has not become apparent to the vaccine industry that a vaccine for HCV was something important. I think it is still something important, I think in many areas of the world a vaccine would be useful, especially because for the same reason we discussed for hepatitis B, you have to treat the patients that have the disease but you also have to prevent new infections and protect the population, but right now this has not appeared as an obvious need and I would say that research and funding for vaccine research is very limited.

For HCV the standard of care is interferon plus ribavirin. Starting form this year we can add a protease inhibitor…

Yes, the new standard of care for genotype 1 is a triple combination of interferon, ribavirin and a protease inhibitor, either telaprevir or boceprevir. I think these two drugs are a progress but it’s still interferon alpha-based and there are some issues and especially issues with tolerance of these combinations. But new new drugs are coming as well new combinations, as we learned at this meeting, previous meetings as well, but here in San Francisco the evidence is very compelling: we can treat and cure hepatitis C pretty easily without interferon. I think the next step will really be the interferon-free era and the question is which drugs, which duration, which patient and this is really we are entering maybe the final step of our quest for the “Holy Grail” of HEP C cure and this one will be which is the best overall interferon-free regimen for all patients infected with HCV. Then we have done that, the same problem we discussed earlier will remain: how do we ensure that access to care is possible for everybody? We have great treatments, they are very expensive, how can we treat everybody? So, it’s the beginning of the end of the story, maybe.

In you speech you presented here in San Francisco a study Phase II that demonstrates the possibility to treat hepatitis C without interferon with a new compound. Can you describe the study?

It’s a study which has been done in patients infected with genotype 2 and 3, they are relatively easy-to-cure patients and the study was based on the use of a cyclophilin inhibitor1, it’s a drug that targets host proteins involved in the HCV replication cycle. This drug was used either alone or in combination with ribavirin without interferon. The patients had the possibility of using interferon if they did not achieve an RVR, rapid virological response, undetectable HCV-RNA at week 4. I think the interesting result there is that with ribavirin and a reasonable dose of alisporivir without interferon, 50% of the patients were able to achieve a rapid virological response on treatment at week 6. We demonstrated that ribavirin added to this, if it’s better to use alisporivir plus ribavirin than alisporivir alone, also demonstrated that some patients who did not have an undetectable HCV/RNA at week 4 got to an undetectable HCV/RNA at week 6 and now, this was interim analysis, we are waiting for the final results of the study and see if these patients will relapse or will achieve a sustained viral response. I am pretty optimistic they will achieve a sustained viral response without interferon, but this will be presented I hope at the next EASL meeting.

And what about the safety profile of this new compound?

The comparison of interferon-containing arms and non-interferon-containing arms gave an obvious advantage for the non-interferon-containing arms. The two major side effects have been associated with the use of alisporivir more frequent than in the non-alisporivir arms were, number one, nausea, which was a little bit more frequent, and, number two, hyperbilirubinemia, which is well-known effect of alisporivir. With the doses that were used in the trial, the elevation in bilirubin levels were pretty acceptable, very few patients did more than 3 times the upper limit of normal and no patient more than 5 times the upper limit of normal. So, on average, it was a modest increase of bilirubin that was dose-dependent and more important in the presence of ribavirin, no other major side effects to report.

So, we will meet in Barcelona to discuss the new results of the study..

I hope that in Barcelona we will be able to show you the sustained viral response results, but I am sure there will be many other studies show in Barcelona and we will probably have a lot to discuss them.

Article found in – HAART and correlated pathologies n. 13

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Hepatitis C: the changing landscape – Interview with Gary Davis

Gary Davis, is the Director of the Division of Hepatology, at Baylor University Medical Center in Dallas and Chair of AASLD’s special interest group on hepatitis C.
I thought that Professor Davis could be in the right position to summarize how the hepatitis C landscape is changed and fast moving. I met him last November, during The Liver Meeting in San Francisco.

In 1991, we were using only one drug, interferon, in fighting against hepatitis C, and it seems we were entering in the future. Now, after twenty years, we have a lot of choices, most of them shortly available. Can you summarize the story of the therapeutics in hepatitis C?

In 1991, we were using standard interferon, which was three times a week. The chance of eradicating the virus was, in retrospect, about 6%. We didn’t know that when we did those studies, we had only ALT levels to go by. We later added pegylated interferon and ribavirin, which improved these responses significantly and then, this last year, we have had the introduction of direct-acting antiviral agents, specifically protease inhibitors, which have allowed us to increase the responses to therapy significantly to the point where we have about 70% of patients who are able to eradicate the infection, that’s cured of the infection.

The landscape of hepatitis C is going to change: how is easy to use these drugs?

Every time we add a drug, we add side effects, we add cost, so it increases the complexity of managing your patients. The payback, of course, of that is that you have greater chance of getting a treatment response and curing your patient, preventing them from getting progressive liver disease.

This Conference is hosting many studies related to costs. How is relevant this kind of issue in the management of hepatitis C?

Cost is very relevant. It’s relevant to the individual patient, it’s probably even more relevant to society. There are abstracts at this meeting talking about ways to better screen for patients, 75% of the patients with hepatitis C don’t know they have it. If we screen better and identify those patients, we bring, in this country, the US, more than a million new patients into physicians’ offices to treat. The cost of doing that, both in personnel, as well as the cost of buying drugs, is phenomenal and we have no way of knowing how we are going to pay for that. So, cost is a real societal issue and access to care is a societal issue and these are becoming as big a challenge as is developing new therapies now.

We know the efficacy of the new drugs that are now approved. What about their safety profile and side effects?

The two protease inhibitors that have just come out in the market, the major side effects are anemia and rash, with one of the drugs, these are problems to manage.
Probably, the most bothersome thing that we have to deal with is drug-drug interactions.
As the infectious disease physicians have been dealing with for years in HIV therapy, these specific antiviral agents go through a complex drug metabolism and they can interfere with the metabolism of other drugs, so that makes management of them very difficult.

In comparison with the HIV field we have a more complex situation, considering that we have to deal with a lot of virus genotypes and with different answers from the virus and the host, regarding these new drugs.

Fortunately, with genotypes 2 and 3, which are the other common genotypes of this infection, we are able to have pretty good responses with interferon and ribavirin themselves. A lot of the new agents are more pan-genotypic, meaning they don’t just work in genotype 1 but they can work in other viral genotypes as well and we expect, as this field develops, that we’ll have more agents that work across genotypes and will improve the responses in all genotypes of hepatitis C.

The patient schedule is going to become more complex: we have to add new pills to the combination interferon plus ribavirin. In this Conference, there are some studies related to the adherence. Many of them are studies related to adherence regarding interferon or standard therapy. We know that interferon produces mood disturbances, depression and other kinds of problems: how is relevant adherence considering the new drugs?

The currently available proteases have to be given every eight hours, that’s difficult for the best patient to be compliant with or adherent with and the new drugs that are in development may not offer a big efficacy advantage, they may not increase the number of patients who clear the virus, but the advantage is they can be taken once a day or twice a day, which is much easier to be adherent to. Hopefully, as we get away from interferon-based therapy, we’ll have less side effects, better tolerated therapies, perhaps taken all by mouth and that should improve adherence as well.
There were presented some studies related to a possible future therapy without interferon…

We hope so. We are not there yet but it’s very encouraging, some of the early results shown at this meeting and the last European study at the Liver Disease meeting were very encouraging that we are going to be able to achieve this. We know we can achieve it in a proportion now with these therapies that are in trial, we need to achieve it in a 100%.
There are many new drugs that are coming, can you list the most hopefully drugs that are arriving?

There are two protease inhibitors that are in Phase III trial in the United States and they should, if all goes well, possibly be approved by the FDA in 2014. There are some drugs right behind that, there is a replicase complex inhibitor, cyclophilin inhibitor, so 2014 and after we’ll see another wave of new agents start to come out, there are many right on the heels of that, so, a lot of drugs coming in the next few years.

It’s interesting that here, in San Francisco, we see downtown, on the buses and trains panel “a new hope, a new era of hepatitis”: when a disease arrives on such display on buses and trains, it means that the story is changing?

Oh, yes, the story is changing a lot. For somebody who has been working in the field for thirty-five years or so, this is very exciting to see the discovery of a virus and within your own career see the potential to eradicate the infection.

Article found in – HAART and correlated pathologies n. 13

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When future will beging? – Hepatitis Debrief, speaking with Gregory T. Everson

In my experience it is quite common to attend medical conference in which, at the end, there are some session called “taking home message” or wrapping up: some key opinion leaders take care to summarize the hot topics of the conference. During the Liver Meeting in San Francisco something of different was made by Gregory T. Everson, Professor of Medicine, University of Colorado School of Medicine, Denver. Prof. Everson was able to provide in about 30 minutes state of the art, what we have learned by the use of the two new PI and what kind of drugs issues and decision we have to face in the next 12-18 months, considering the use of multiple drugs with the goal of obtaining viral clearance and interferon free regimes:

During this Conference we had a lot of presentations regarding new future drugs candidate for hepatitis C, but this year 2011 we had the first two protease inhibitors in the market. In your wrap-up at the end of the Conference, you started explaining what we have learned from the use of these new two drugs…

Boceprevir and telaprevir are the two drugs you are referring to. They are protease inhibitors and they both work at exactly the same site for the hepatitis C virus. What we found is that those two drugs, when added to peginterferon and ribavirin, each individually of course, increases the chance to clear HEP C from about 40% up to 75%. So, there has been about an overall 30% improvement in the chance to clear hepatitis C with the two new protease inhibitors. The most important thing for doctors and patients, though, is to understand that these drugs have to be given with peginterferon and ribavirin, they can never ever be given alone. If you take the drugs alone, you’ll become resistant and it won’t work, you have to take those drugs with peginterferon and ribavirin, that’s why we use the term “triple therapy”: peginterferon, ribavirin with either telaprevir or boceprevir.

But we have also learned is that the backbone, the answer to interferon is relevant in terms of the final sustained biological response.

Yes, that’s correct. Studies at this meeting actually addressed that particular point, which is: it’s the background of interferon responsiveness that predicts who best will be able to respond to treatment with the triple therapy. In addition, another big factor predicting response is how much scar tissue build-up there is in the liver, how much fibrosis, and the patients who have extensive fibrosis or cirrhosis seem to have a lower ability to respond to triple therapy and clear hepatitis C and, if you combine those two factors together, a poor response to interferon and a lot of fibrosis in the liver, cirrhosis, those two factors together really knock down the ability clear hepatitis C with triple therapy. In fact, in that particular subgroup, even though the numbers are relatively small, it isn’t that much better than just peginterferon and ribavirin alone, both running around 10 to 15% chance to achieve SVR. The point is that the populations with the poorest response to interferon are: prior treatment failures, people when given interferon who don’t run their hepatitis C RNA down, underlying cirrhosis, perhaps African-American or black race and, we haven’t much data, but perhaps even in Latinos there is a factor, but so far most of the data with telaprevir- and boceprevir-based triple therapy suggest that Latinos respond just about as well as Caucasians.

Many studies at this meeting are related to the costs about these drugs…

Yes, cost is definitely a factor. I mean, obviously access to the treatment is going to be dictated by ability to pay or coverage of being insured or having some third-party payer mechanism. So, there have been many studies at this meeting about cost effectiveness.
The usual parameter or threshold that is used for cost effectiveness is somewhere around 50.000 dollars – you know? – for improved outcomes and, with both telaprevir and boceprevir they seem to exceed those thresholds, I mean stay under those thresholds, so that the quality of life gained by clearing HEP C, the reduction in risk for liver-related complications, is so great that it offsets the cost factor in terms of the cost effectiveness of the treatment. Nonetheless, it would be awfully nice if we could run down the cost of these protease inhibitors to the point where it becomes more widely available, more universally available and hopefully with new drug development there will be more competition and more price adjustment and hopefully that will come and reduce the cost down, hopefully.

We have a lot of new protease inhibitors in the pipeline. Can you list the most common problems or issues related to this class of drugs?

The common problem with protease inhibitors is the risk of resistance, so if you are resistant to one you may become resistant to others. The good news on that is that the more potent the protease inhibitor, the less likely these resistant variants will emerge. Also, the good news about most of the resistant variants is that they are sensitive to interferon and ribavirin, so the triple therapy with the protease inhibitors seems to keep most of the resistance issues in abeyance. And then, if we add other drugs such as polymerase inhibitors, NS5A inhibitors, there is no cross-over in the resistance, so that using double drug therapies, triple drug therapies may over time actually eliminate the resistance issue. The other thing with protease inhibitors, there are, you know there is always some side effects with these drugs. The side effects are generally relatively mild, occasionally they can be severe, with telaprevir rash can be an issue, with both drugs anemia can be an issue and with boceprevir some of the patients complain of a pretty significant foul taste in the mouth. The new drugs, also some of them have some rash issues, some of them have some problems with gastrointestinal upset and some of them have some issues with even liver blood test elevations. Most of it seems to be relatively benign because the treatment courses are getting shorter and shorter, so the exposure to a patient may be less and less and hopefully that will translate into less toxicity.

And also there will be a possible reduced pill burden…

Yes. You know, right now the number of pills required with the current triple therapy regimens is pretty high. I mean, the ribavirin pill use per day is about, depending on the preparation, up to 6 pills a day and then with telaprevir it’s another 6 pills a day and boceprevir is another 12 pills a day, so, depending on what regimen you are on, you got a fair number of pills to take every day and it’s very difficult for a lot of people to do that. The other part of it is that it’s recommended that you have meals with each of the doses and I had some patients who complain that they are gaining weight on the treatment because of the amount of meals they are eating and they are not used to eating as much and that’s in direct contradistinction to when, in the peginterferon and ribavirin days when the main complaint was some weight loss and loss of appetite and now we are forcing them to eat and the good news is that they are keeping their weight up, that bad news in America they are getting a little too heavy.

In your talk you mentioned the results of “quad” therapy, that were presented during this Conference..

“Quad” therapy is peginterferon and ribavirin with two direct-acting antivirals and it’s a promising strategy in the fact that it seems to shorten the duration, it may also improve the chance to be cured of HEP C, but all the studies presented at this year’s Liver Meeting are what we call phase II studies, and so you have to be very cautious about projecting from phase II studies to what’s going to happen in the bigger trials and in the future, but it’s promising, there is no question about it.

There also new drug classes arriving just behind the corner, I am referring to the drugs that address host factors…
Exactly. In addition to these drugs that are specifically targeting the virus, there is a number of new ideas about how to ramp up the host antiviral activity, and so cyclophilin inhibitors, inhibitors of the uptake process of the virus into the liver and even microRNA strategies are evolving and there were several abstracts at this meeting presented on these evolving new strategies.

Is it possible to speculate when the future will happen?

Well, I don’t claim to see the future, the projections are perhaps that we may start to see some of these drugs emerge out of the Phase III trials, as early as 2014, possibly even in the last quarter of 2013, but there is rarely a smooth road to full approval of therapy, so I think somewhere around by the year 2015 we should be seeing additional drugs in the armamentarium of medications to treat patients with hepatitis C.

Last question: in 1991 we started with the monotherapy of interferon and now we are in a new condition to decide how many drugs combine and when these drugs must be use. Should we think about possible future as a time during which therapy will be without interferon?

I think everyone will be happy, including the doctors and especially the patients. I think the future of this is going to be where physicians will sit with their patient and they will work together to devise the best treatment plan. Hopefully, we are going to have many, many drugs to pick from that all of which are highly effective and each with their own specific characteristics that make then desirable for a given patient. So, I think we are going to see patient-centered care and patient-centered approaches to the treatment of HEP C in the future.

Article found in – HAART and correlated pathologies n. 13

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HCV drugs: a sea of options where we sail – Interview with Mark Thursz

Results of research must reach people who are in need. But when we speak about HCV we see only the top of the iceberg – “in Europe we probably have identified less than 50% of those patients infected”- floating in a sea of possible new choices represented by many new coming drugs: this is the problem we are facing now, according to Mark Thursz, professor of hepatology at Imperial College, London and currently vice-secretary of the European Association for Study of the Liver (EASL). In this role he has special responsibility for EU policy and advocacy in Brussels. I met professor Thursz during last EASL meeting in Berlin, last April.

The feeling is that now we living the first days of the new era for the therapy of hepatitis thanks to protease inhibitors. Before the use of these new drugs, what are the unmet needs with the current therapies?

Obviously the problem we have with the current therapies is the side effect profile, the success rates of treatment, particularly in the difficult-to-treat genotypes, genotype 1 and genotype 4, and we also can’t use interferon and ribavirin in patients who have got advanced liver disease, so this is something that we need to be thinking about in the future.
Going slightly broader, though, one of the major issues that we have is actually finding the patients: that may seem a silly concept but, actually, if you want to reduce the burden of liver disease that is caused by hepatitis C you have to identify the patients with the infection and then they can be put through treatment protocols, but at the moment in Europe we probably have identified less than 50% of those patients infected and, because it’s a asymptomatic infection, they don’t feel as though they are ill, then patients don’t necessarily come forward, so we need the public health authorities around Europe to do something about that.

The first two new drugs approved are protease inhibitors. In HIV field, protease inhibitors made possible HAART, a real revolution. Now HIV infection is a chronic condition, thanks to the HAART. Do you think that new anti HCV drugs will do the same?

These are the first class of drugs to get into our clinical practice and protease is important in hepatitis C particularly because the protease has effects on the immune response to the virus, so by inhibiting this particular viral enzyme actually you can let some, or theoretically at least, you let some of the natural immune responses help you to clear the viral infection.

The first two drugs are boceprevir and telaprevir: what are the main advantages?

The both of them have excellent sustained viral response rates and obviously in hepatitis C, unlike HIV, a sustained viral response means a cure and they increase the rate substantially, both in treatment-naive individuals but, in particular, as we have heard this week, in patients who have previously had treatment with pegylated interferon and ribavirin and then failed treatment and that’s a group of patients that every Liver Unit or every Infectious Diseases Unit around Europe they have a large cohort of those patients and they are desperately in need of something to stop their liver sliding down to cirrhosis.

These drugs must be used in combination with current therapies…

Yes, that is true, so at the moment we are adding in direct antivirals to our standard-of-care, so the standard-of-care of pegylated interferon and ribavirin, and one thing I should say is actually in many patients the addition of a direct antiviral allows us to shorten the duration of treatment, which is good for patients, so we have been treating genotype- 1 infection for 48 weeks, now that comes down to about 24 weeks in many patients, so a big improvement.

Maybe we are going to face a new issue in HCV, that is viral resistance: how to deal with this?

This is true, so any direct antiviral will generate resistance. We already know it happens in the protease inhibitors and the polymerase inhibitors, we anticipate it in most classes of drugs and is well documented in the HIV field. I think the problem will need to be addressed by using multiple classes of drugs in due course, what we might, once we have got a handle on this problem, what we might be able to anticipate is using probably three different classes of drugs in a potentially interferon-free regime in the future.

Is the interferon-free therapy the future goal?

Here in Berlin at the International Liver Congress we have one abstract been presented which is a tiny, tiny little study but is really the light at the end of the tunnel for those people who are not going to tolerate pegylated interferon and ribavirin, so this is a study in which a small group of patients were given a protease inhibitor and a NS5A inhibitor and some of them cleared the virus during treatment. So, it’s early days, but it suggests that interferon-free regimes will be viable in the future, which is what many of us have been looking forward to.

This Conference occurs in an historical phase of financial crisis, we are speaking about new drugs and maybe we are afraid about prices of these drugs.

So, this is always a problem, new drugs mean better quality of healthcare but more expensive healthcare, but in this situation we have to pay attention to the fact that actually the cost of treating somebody who develops end-stage liver disease, liver cancer and then requires transplantation, as well as the socioeconomic cost of somebody being that unwell, are extremely high, so you have to invest now in clearing their infection in order to reduce the future cost and the future health burden because a patient is terminally ill or requires transplantation and if they have a transplant then they permanently need treatment.

At the beginning of this conversation, you said that there is a large amount of hepatitis cases or infections that are not recognized, at the same time we have new tools in order to reduce the viral burden, what is, in terms of public health, the potential impact of these new drugs in fighting against hepatitis?

It is crucial to identify a patient who has got chronic viral hepatitis, but if you were to identify them and then tell them there was no successful treatment, then you wouldn’t really be helping that individual, but what we can offer those people now is actually a sensible chance of clearing the infection, so you can then, you can go to screen a population, identify people who have got the infection and offer them a treatment that is 80% successful, even if they have got a hard-to-treat genotype. So, the impact is partly on the attitude of the patients because many patients say “Well, if you give me a treatment that is only 50/50, then I am not going to take it, thank you very much”, now more patients are going to accept treatment, that means we can make an impact on the overall disease burden.

Article found in – HAART and correlated pathologies n. 13

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